A process for the preparation 2,2-dimethyl-5-(4-chlorobenzyl)-cyclopentanone, a key intermediate in the production of the anti-fungal agent metconazole is described in U.S. Pat. No. 5,028,254 and U.S. Pat. No. 4,938,792. Metconazole is highly effective for the control of a wide range of foliar diseases caused by phytopathogenic fungi which damage a number of important agronomic crops. Alternative, effective methods for the preparation of metconazole contribute to the enhanced availability of this useful fungicidal agent. Although, methods such as those mentioned hereinabove are known, said methods require extreme low temperature conditions for the prepartion of the intermediate 2,2-dimethyl-5-(4-chlorobenzyl) cyclopenanone.
Therefore, the preparation of 2,2-dimethyl-5-(4-chlorobenzyl)cyclopentanone continues to be studied for new and improved procedures which are more efficient and environmentally benign.
It is an object of the present invention to provide an improved process for the preparation of 2,2-dimethyl-5-(4-chlorobenzyl)cyclopentanone.
It is a further object of the invention to provide a compound, 5-(4-chlorobenzyl)-5-cyano-2,2-dimethylcyclopentanone, useful in an improved manufacture of metconazole.
There is provided a process for the preparation of 2,2-dimethyl-5-(4-chlorobenzyl)cyclopentanone (I) 
which comprises the following steps:
(a) reacting isobutyronitrile with 1-bromo-3-chloropropane in the presence of a first base in a non-polar solvent at a temperature of about 15xc2x0to 65xc2x0C. to afford 5-chloro-2,2-dimethylpentanenitrile;
(b) treating said 5-chloro-2,2-dimethylpentanenitrile with a cyanide-delivering reagent in the presence of a phase-transfer catalyst to form 2,2-dimethyladiponitrile;
(c) cyclizing said 2,2-dimethyladiponitrile in the presence of a second base in a non-polar solvent to afford 3,3-dimethyl-2-amino-1-cyanocyclopentene;
(d) hydrolyzing said 3,3-dimethyl-2-amino-1-cyanocyclopentene; in the presence of an acid to give 5-cyano-2,2-dimethylcyclopentanone;
(e) treating said 5-cyano-2,2-dimethylcyclopentanone with 4-chlorobenzyl chloride in the presence of a third base in a polar aprotic solvent to form 5-(4-chlorobenzyl)-5-cyano-2,2-dimethylcyclopentanone; and
(f) hydrolyzing said 5-(4-chlorobenzyl)-5-cyano-2,2-dimethylcyclopentanone in the presence of an acid to give the desired compound 5-(4-chlorobenzyl)-2,2-dimethylcyclopentanone.
The invention further provides the compound, 5-(4-chlorobenzyl)-5-cyano-2,2-dimethylcyclopentanone.
Previously described conditions for effecting the alkylation of isobutyronitrile with 1-bromo-3-chloropropane require the use of polar solvents and a reaction temperature of xe2x88x9278xc2x0 C. (S. S. Kulp, V. B. Fish and N. R. Easton, Can. J. Chem., 1965, 43,2512; M. N. Romanelli, F. Gaultiere, R. Mannhold and A. Chiarini, Farmaco, 1989, 44, 449). This temperature requirement is not readily attainable on a large manufacturing scale. Surprisingly, it has now been found that the alkylation of isobutyronitrile in a non-polar solvent,in the presence of a base such as lithium bis(trimethylsilylamide) or lithium dimethylamide proceeds in high yield when conducted at temperatures up to 65xc2x0 C., thus permitting a more efficient and effective manufacturing procedure.
Advantageously, the present invention provides an effective and practical method for the preparation of 5-(4-chlorobenzyl)-2,2-dimethycyclopentanone, a key intermediate in the production of the antifungal agent metconazole.
In accordance with the process of the invention isobutyronitrile (III) is alkylated with at least one molar equivalent of 1-bromo-3-chloropropane in a non-polar solvent in the presence of a first base to yield 5-chloro-2,2-dimethylpentanenitrile (IV); said 5-chloro-2,2-dimethylpentanenitrile (IV) is treated with a cyanide-delivering reagent in the presence of a phase-transfer catalyst (Ptc) to yield 2,2-dimethyladiponitrile (V); said 2,2-dimethyladiponitrile (V) is cyclized in the presence of a second base in a non-polar solvent to form 3,3-dimethyl-2-amino-1-cyanocyclopentene. Advantageously, the thus-formed 3,3-dimethyl-2-amino-1-cyanocyclopentene (VI) may be carried on without isolation or purification to acid hydrolysis to form 5-cyano-2,2-dimethylcyclopentanone (VII). Said cyclopentanone (VII) is then alkylated with 4-chlorobenzyl chloride in the presence of a third base in a polar aprotic solvent to give the intermediate 5-(4-chlorobenzyl)-5-cyano-2,2-dimethylcyclopentanone (II). Finally, said pentanone is hydrolyzed with acid to provide 5-(4-chlorobenzyl)-2,2-dimethylcyclopentanone (I). The process is depicted in Flow Diagram I. 
Non-polar solvents suitable for use in the process of the invention are essentially water-free solvents such as aromatic hydrocarbons (e.g. toluene, benzene, xylene, naphthalene or the like, preferably toluene), halogenated aromatic hydrocarbons (e.g. chlorobenzene, dichlorobenzene or the like), hydrocarbons (e.g. pentane, hexane or the like), halogenated hydrocarbons (e.g. chloroform, methylene chloride, dichlorethane, or the like, or any of the conventional, preferably water immiscible, organic non-polar solvents.
Preferred non-polar solvents suitable for use in the process of the invention are hydrocarbons and aromatic hydrocarbons such as hexane, heptane, toluene, ethylbenzene or the like.
Polar aprotic solvents suitable for use in the inventive process are dimethyl formamide, dimethylsulfoxide, tetrahydrofuran, diethyl ether, or the like.
Preferred polar aprotic solvents suitable for use in the process of the invention are dimethylformamide and dimethylsulfoxide.
Bases suitable for use as the first base in the inventive process are alkali metal amides, such as lithium amide, lithium dimethylamide, sodium bis(trimethylsilyl)amide, magnesiochlorodiethylamide (Et2NMgCl), preferably lithium bis(trimethylsilyl)amide or lithium amide.
Bases suitable for use as the second base in the inventive process are alkali metal alkoxides, such as sodium or potassium C1-C4 alkoxide, preferably sodium t-butoxide.
Bases suitable for use as the third base in the inventive process are alkali metal hydrides, such as sodium, potassium or lithium hydride, preferably sodium hydride.
Bases may be present in amounts ranging from catalytic to excess amounts such as 10 mole % to 4.0 molar excess.
Acids suitable for use in the process of the invention include strong mineral acids such as HCl, HBr or H2SO4, preferably H2SO4.
The term catalysis refers to the enhancement of the rate of a reaction by the presence of a base when the base is left unchanged by the overall reaction. A phase transfer catalyst is a compound which facilitates the transfer of reactants across the interface of a two-phase organic-water system thereby enhancing the rate of reaction in said systems.
Phase-transfer catalysts suitable for use in the process of this invention are tetrabutylammonium hydrogen sulfate, tetrabutylammonium bromide, benzyltriethylammonium chloride, or the like, preferably tetrabutylammonium hydrogen sulfate.
In actual practice, isobutyronitrile (III) is alkylated with at least one molar equivalent of 1-bromo-3-chloropropane in a non-polar solvent, preferably a hydrocarbon, more preferably hexane, in the presence of a first base, preferably an alkali metal amide, more preferably lithium bis(trimethylsilylamide) or lithium dimethylamide, to yield 5-chloro-2,2-dimethylpentanenitrile (IV); said 5-chloro-2,2-dimethylpentanenitrile (IV) is treated with a cyanide-delivering reagent, preferably an alkali metal cyanide, more preferably sodium cyanide, in the presence of a phase-transfer catalyst, preferably tetrabutylammonium hydrogen sulfate, to yield 2,2-dimethyladiponitrile (V); said 2,2-dimethyladiponitrile (V) is cyclized in the presence of a second base, preferably an alkali metal alkoxide, more preferably sodium t-butoxide, in a non-polar solvent, preferably an aromatic hydrocarbon, more preferably toluene; the thus formed 3,3-dimethyl-2-amino-1-cyanocyclopentene (VI) advantageously may be carried on without isolation or purification to acid hydrolysis, preferably with a strong mineral acid, more preferably with sulfuric acid, to form 5-cyano-2,2-dimethylcyclopentanone (VII); said cyclopentanone (VII)is alkylated with 4-chlorobenzyl chloride in the presence of a third base, preferably an alkali metal hydride, more preferably sodium hydride, in a polar aprotic solvent, preferably N,N-dimethylformamide, to give the intermediate compound 5-(4-chlorobenzyl)-5-cyano-2,2-dimethylcyclopentanone (II); said compound is hydrolyzed with acid, preferably strong mineral acid, more preferably sulfuric acid, to provide the desired product 5-(4-chlorobenzyl)-2,2-dimethylcyclopentanone (I).
In order to present a clear understanding of the invention, the following examples are set forth below. These examples are merely illustrative, and are not to be understood as limiting the scope and underlying principles of the invention in any way.